Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of glucagon on water and electrolyte transport in the kidney were investigated on hormone-deprived rats, i.e. thyroparathyroidectomized diabetes insipidus Brattleboro rats infused with somatostatin. Glucagon consistently inhibited the reabsorption of water and Na+, Cl-, K+ and Ca2+ along the proximal tubule accessible to micropuncture, leaving the reabsorption of inorganic phosphate (Pi) untouched. In the loop, besides its previously described stimulatory effects on Na+, Cl-, K+, Ca2+ and Mg2+ reabsorption, glucagon strongly inhibited Pi reabsorption, very probably in the proximal straight tubule. These effects resulted in a significant phosphaturia and considerable reductions of Mg2+ and Ca2+ excretions. The effects of glucagon at both the whole kidney and the nephron levels are very similar to those previously described for calcitonin. In the absence of an adenylate cyclase system sensitive to glucagon and calcitonin in the rat proximal tubule, and from the analogy of their physiological effects with those elicited by parathyroid hormone, it is suggested that glucagon and calcitonin exert their inhibitory effects on Na and Pi reabsorption in the proximal tubule through another pathway, which could be the phosphoinositide regulatory cascade.
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PMID:Glucagon inhibits water and NaCl transports in the proximal convoluted tubule of the rat kidney. 177 68

Galanin, an ubiquitous neuropeptide, was recently shown to inhibit somatostatin release by the rat islet tumor cell line, Rin-m. By using the clonal pancreatic delta cell line Rin14B, originating from Rin-m cells, we were able to identify the presence of one type of specific galanin-binding site of high affinity (Kd = 1.6 nM; maximal binding capacity = 270 fmol/mg protein) and high specificity for the peptide. Binding of 125I-galanin to these receptors was time-dependent and highly sensitive to guanine nucleotides. Using the cross-linker disuccinimidyl tartrate, covalent linking of the galanin receptor to 125I-galanin in membranes from Rin14B cells, followed by SDS/PAGE analysis of membrane proteins, indicated that the galanin receptor is a protein of 54 kDa. 0.1-100 nM galanin also exerted a marked inhibitory effect on the cAMP-production system under basal conditions, as well as in the presence of the pancreatic peptide glucagon. At a maximal dose, galanin induces a 90-100% decrease of basal and glucagon-stimulated cAMP production levels, with a median inhibition concentration (IC50) of 3 nM galanin. The direct inhibitory effect of galanin on the adenylate cyclase activity in Rin14B cell membranes was also demonstrated (IC50 = 3 nM galanin). The inhibitory effect of galanin on the basal and glucagon-stimulated cAMP production in Rin14B cells was reversed by pertussis toxin. The toxin was also shown to specifically ADP-ribosylate a protein of 41 kDa in membranes from Rin14B cells. Taken together, these data show that the pancreatic delta cell line Rin14B expresses high affinity galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production system.
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PMID:A clonal rat pancreatic delta cell line (Rin14B) expresses a high number of galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production pathway. 184 83

Somatostatin (somatotropin release inhibiting factor; SRIF) has widespread functions as a modulator of neural activity as well as of endocrine and exocrine secretion. In the present paper, the binding characteristics of somatostatin receptors have been investigated in rat long bones using the stable analogue, 125I-SDZ 204-090, as a ligand. Binding studies revealed the presence of a single class of high-affinity binding sites for 125I-SDZ 204-090 on cells prepared from neonatal rat long bones with an equilibrium dissociation constant (KD) of 70.1 +/- 8.2 pM (n = 3). An excellent correlation was found between the ability of various somatostatin analogues to inhibit growth hormone in pituitary cells and to displace the binding of 125I-SDZ 204-090 to the bone cell preparation, indicating that the receptors are very similar, if not identical. The localization of the somatostatin-binding sites was examined by autoradiography after labelling in vitro and in vivo. The binding sites were shown by both procedures to be selectively localized to the metaphysis of rat long bones. The labelling experiments in vivo indicate that these receptors can be reached in the living animal by circulating somatostatin analogues. In addition, the analogue SMS 201-995 inhibited the forskolin-stimulated adenylate cyclase activity in bone cell suspensions. These results suggest that somatostatin could be an important regulatory factor in bone metabolism.
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PMID:Identification and characterization of somatostatin receptors in neonatal rat long bones. 196 33

The effects of CRH and somatostatin (SRIH) on adenylate cyclase (AC) activity, intracellular free calcium concentrations [( Ca2+]i) and in vitro ACTH release were investigated in six human ACTH-secreting pituitary adenomas. In all tumors, CRH induced a marked stimulation (from 69-210% at 10 nM), whereas SRIH caused a definite inhibition (from 29-50% at 100 nM) of membrane AC. When added together, CRH and SRIH caused a purely additive effect on AC. In adenomatous corticotrophs CRH (10 nM) caused [Ca2+]i to rise from 160 +/- 30 nM (mean +/- SD) to 410 +/- 95 nM. CRH-induced transients were biphasic, with an initial peak predominantly due to redistribution from intracellular Ca2+ stores and a secondary phase due to Ca2+ influx. The effects of CRH on [Ca2+]i were totally independent of the stimulation of AC. In fact, cAMP-elevating agents other than CRH did not modify [Ca2+]i. SRIH (100 nM) decreased resting [Ca2+]i (approximately 20-40%) as well as [Ca2+]i rises induced by CRH, arginine vasopressin, or high K+. The effect of SRIH on [Ca2+]i was maintained in presence of high cAMP levels, while was totally abolished after pertussis toxin pretreatment. CRH (10 nM) stimulated ACTH release (from 22.5 +/- 3.5 to 45.0 +/- 8.5 pmol/L) by an extent similar to that elicited by calcium ionophore and forskolin. By contrast, SRIH (0.1 microM) inhibited both basal and CRH-stimulated ACTH release. In conclusion, in human adenomatous corticotrophs SRIH exerts an inhibitory action by reducing both AC activity and, independently, [Ca2+]i. In this way, SRIH can efficiently counteract the stimulatory action of CRH that in these cells involves activation of both cAMP and Ca2+ pathways.
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PMID:Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca2+ levels by somatostatin in human corticotropin-secreting pituitary adenomas. 197 Aug 28

The effects of endogenous hypothalamic neurohormones and activators of second messenger signalling systems on the secretion of GH and on cell content of GH mRNA of cultured bovine adenohypophysial cells were studied. Synthetic bovine GH-releasing factor (bGRF; 100 nmol/l) increased secretion of GH by bovine adenohypophysial cells five-fold relative to control. Forskolin (an adenyl cyclase activator; 10 mumol/l) and the synthetic cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) increased secretion of GH by 1.9- and 1.7-fold respectively, relative to control. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA), provided at 1 mumol/l or 10 nmol/l, increased GH secretion by 6.6- and four-fold respectively, relative to control. Somatostatin-14 (SRIF-14) attenuated basal, bGRF-, forskolin- and dbcAMP-stimulated secretion of GH by 40, 49, 47 and 67% respectively, but did not, however, diminish PMA-stimulated GH secretion. The content of GH mRNA in cultured bovine adenohypophysial cells increased 2.2-, 1.7- and 3.2-fold by administration of bGRF, forskolin and PMA respectively, relative to control. Although GH mRNA content was unchanged by SRIF-14 treatment relative to control, SRIF-14 did reduce bGRF-stimulated bGH mRNA content by 67%. This study demonstrates that mechanisms subserving GH secretion in bovine adenohypophysial cells (e.g. adenyl cyclase and protein kinase C) may be coupled with mechanisms which regulate expression of the GH gene or with factors affecting message stability.
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PMID:Modulation of growth hormone (GH) secretion and GH mRNA levels by GH-releasing factor, somatostatin and secretagogues in cultured bovine adenohypophysial cells. 197 Oct 2

The interaction of adrenergic and peptide receptors linked to adenylate cyclase and the inhibition by bioactive peptides of stimulated cyclic AMP production has been investigated in intact, excised rabbit ciliary processes. Cyclic AMP production stimulated by isoproterenol, vasoactive intestinal peptide, or forskolin was inhibited by the biologically active peptides neuropeptide Y, somatostatin, and the synthetic somatostatin analogue SMS 201-995. IC50s determined from dose-response curves of inhibition are consistent with the known abilities of these ligands to modulate cyclic AMP and physiological responses in other tissues. Inhibition by neuropeptide Y or SMS 201-995 was unaffected by the specific alpha 2-adrenergic antagonist yohimbine, which shows that peptide inhibition is not occurring via peptide binding to the inhibitory alpha 2-adrenergic receptor. These results suggest that endogenous peptides may participate in modulation of cyclic AMP production and subsequent physiological events influenced by cyclic AMP levels in rabbit ciliary processes by inhibiting stimulated cyclic AMP synthesis.
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PMID:Neuropeptide Y and somatostatin inhibit stimulated cyclic AMP production in rabbit ciliary processes. 197 Dec 7

Receptor-dependent and -independent regulation of gastrin secretion from cultured human antral G cells was investigated. Human antral mucosal cell preparations that were enriched for G cells were obtained by sequential incubations with collagenase and ethylenediaminetetraacetic acid, centrifugal elutriation, and short-term culture. After a 2-day incubation period, gastrin- and somatostatin-containing cells accounted for 15% and 5%, respectively, of the total adhered-cell population. Forskolin, A23187, and beta-phorbol 12 myristate 13-acetate stimulated basal gastrin secretion from cultured human G cells in a concentration-dependent fashion. These results indicate that gastrin release could be mediated by elevations in cytosolic cyclic adenosine monophosphate levels, calcium influx, or activation of protein kinase C. A direct stimulatory role for bombesin- and gastrin-releasing peptide was supported by experiments showing concentration-dependent enhancement of gastrin release by bombesin from 0.01 fmol/L to 10 nmol/L. The putative bombesin antagonist [Leu13-psi-CH2NH-Leu14] bombesin augmented basal gastrin levels by itself and produced weak inhibition of bombesin-induced gastrin secretion from human antral G cells. Somatostatin potently suppressed forskolin- and bombesin-mediated gastrin release but did not significantly alter basal gastrin levels. These results suggest that bombesin and somatostatin directly activate and inhibit G-cell function via specific and sensitive receptors. Furthermore, the adenylate cyclase and phosphatidyl inositide second messenger systems seem to be intracellular mediators of gastrin secretion from human antral G cells.
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PMID:Gastrin secretion from human antral G cells in culture. 197 10

Somatostatin, a cyclic tetradecapeptide, is both a hypothalamic hormone and a paracrine peptide, with effects on many tissues. Despite the fact that somatostatin can inhibit various cellular events in a number of cell lines, somatostatin is a constituent of medium defined for optimal growth of FRTL5, a line of differentiated and nontransformed rat thyroid follicular cells. In the present study we have evaluated the role of somatostatin in the control of DNA synthesis in FRTL5 cells and have investigated the mechanisms of somatostatin interaction with pathways stimulated by TSH and insulin-like growth factor-I (IGF-I). Somatostatin inhibits TSH-stimulated DNA synthesis and cell proliferation in FRTL5 cells. Maximal effects are observed at somatostatin concentrations of 0.1-10 ng/ml, and the effects are diminished at somatostatin concentrations above 10 ng/ml. Somatostatin also inhibits (Bu)2cAMP-stimulated DNA synthesis, suggesting that the loci of somatostatin action are both proximal and distal to activation of adenylate cyclase. Somatostatin also inhibits DNA synthesis stimulated by insulin-like growth factor-I (IGF-I), a pleiotropic growth factor that works through non-cAMP-dependent pathways. The somatostatin analog octreotide is more potent than native somatostatin in inhibiting DNA synthesis stimulated by either TSH or IGF-I. Somatostatin does not alter TSH or IGF-I binding to FRTL5, demonstrating that somatostatin affects the postreceptor signal transduction pathways stimulated by these factors. We conclude that 1) the use of somatostatin in hormone-supplemented medium for FRTL5 is unnecessary and may inhibit cell growth; 2) somatostatin can inhibit the direct effects of IGF-I on peripheral tissues in addition to its ability to interfere with IGF-I synthesis by inhibiting the synthesis and release of pituitary GH; and 3) somatostatin is a useful tool for dissecting the pathways involved in mediating differentiated function and growth of FRTL5 cells.
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PMID:Somatostatin inhibits deoxyribonucleic acid synthesis induced by both thyrotropin and insulin-like growth factor-I in FRTL5 cells. 197 59

Calcium (Ca2+) ion concentrations that are achieved intracellularly upon membrane depolarization or activation of phospholipase C stimulate adenylate cyclase via calmodulin (CaM) in brain tissue. In the present study, this range of Ca2+ concentrations produced unanticipated inhibitory effects on the plasma membrane adenylate cyclase activity of GH3 cells. Ca2+ concentrations ranging from 0.1 to 0.8 microM exerted an increasing inhibition on enzyme activity, which reached a plateau (35-45% inhibition) at around 1 microM. This inhibitory effect was highly cooperative for Ca2+ ions, but was neither enhanced nor dependent upon the addition of CaM (1 microM) to EGTA-washed membranes. The inhibition was greatly enhanced upon stimulation of the enzyme by vasoactive intestinal peptide (VIP) and/or GTP. Prior exposure of cultured cells to pertussis toxin did not affect the inhibition of plasma membrane adenylate cyclase activity by Ca2+, although in these membranes, hormonal (somatostatin) inhibition was significantly attenuated. Maximally effective concentrations of Ca2+ and somatostatin produced additive inhibitory effects on adenylate cyclase. The addition of phosphodiesterase inhibitors demonstrated that inhibitory effects of Ca2+ were not mediated by Ca2(+)-dependent stimulation of a phosphodiesterase activity. These observations provide a mechanism for the feedback inhibition by elevated intracellular Ca2+ levels on cAMP-facilitated Ca2+ entry into GH3 cells, as well as inhibitory crosstalk between Ca2(+)-mobilizing signals and adenylate cyclase activity.
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PMID:Potent and cooperative feedback inhibition of adenylate cyclase activity by calcium in pituitary-derived GH3 cells. 197 2

The mechanisms involved in inhibition of insulin secretion by somatostatin and noradrenaline were compared in order to establish whether the receptors for these agents are coupled to similar effector systems in the pancreatic B cell. Both agents significantly reduced forskolin-induced adenylate cyclase activity in islet homogenates, although noradrenaline was more effective than somatostatin. The capacity of noradrenaline to inhibit insulin secretion was largely unaffected by agents that increase intracellular cyclic AMP, whereas the effect of somatostatin as an inhibitor was markedly reduced under these conditions. Both noradrenaline and somatostatin inhibited the stimulation of insulin secretion induced by K+ depolarization, but different mechanism were involved. Somatostatin significantly inhibited K(+)-stimulated 45Ca2+ efflux and influx in islets, while noradrenaline exerted only a minor influence on these processes. The data indicate that noradrenaline controls insulin secretion by a mechanism which operates beyond the level of intracellular messenger generation. In contrast, somatostatin exerts at least part of its inhibitory effect on insulin secretion by directly controlling islet cell Ca2+ influx in a manner which may be regulated by cyclic AMP.
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PMID:Evidence for differential effects of noradrenaline and somatostatin on intracellular messenger systems in rat islets of Langerhans. 197 36


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